The precise dynamic property of glucagon secretion in response to glucose concentration has not yet been elucidated, since in in vitro studies using pancreatic islets, the co-existence of pancreatic B cells modifies the mode of glucagon secretion, and in in vivo studies, the exogenous insulin administration greatly affects pancreatic A cell function.
In this study, to clarify the dynamic property of glucagon secretion in response to glucose concentration and the ability of glucagon to raise hepatic glucose production, an artificial endocrine pancreas was employed as a research tool. Our originally developed artificial endocrine pancreas prepared the glucagon and/or glucose infusion algorithm as the counterregulatory system.
The principle of glucagon and glucose infusion algorithm is set as the proportional plus derivative modes of action to blood glucose concentration with time delay constant, as follows;
Gn.I.R.(t)=Gp[BGp-BG(t-τ)]+Gd[-ΔBG(t-τ)]+Gc
G.I.R.(t)=Cp[BGp-BG(t-τ)]+Cd[-ΔBG(t-τ)]
where Gn.I.R. (t) and G.I. R. (t) are glucagon infusion rate and glucose infusion rate, respectively. BGp is the projected value of blood glucose concentration, and BG (t) and ΔBG are blood glucose concentrations and the rate of change in blood glucose concentration at time t respectively.
Gp and Gd are coefficients for glucagon infusion, and Cp and Cd are those for glucose infusion. Gc is the constant for basal glucagon supplementation. τ(min) is the time delay constant for glucagon and glucose infusion.
In a depancreatized dog, the blood glucose concentration was maintained at the normoglycemic level with intraportal insulin infusion using this artificial endocrine pancreas for at least one hour, then hypoglycemia was induced by iv bolus insulin injection (0.1U/kg). Glucagon was infused intraportally or glucose was infused into the peripheral vein when the counterregulatory system was operated according to each of these algorithm by variously changing the parameters.
1) In the intraportal glucagon infusion algorithm, with the optimal parameters based on proportional plus derivative modes of action with a 10-min time delay (Gp/Gd/Gc/τ=0.2/ 0.4/0.6/10), both the blood glucose response curves and plasma glucagon profiles simulated those seen in normal dogs. On the other hand, glucagon infusion based only on the proportional action failed to simulate the blood glucose response and plasma glucagon profile of normal dogs.
2) When glucose was infused on the basis of the proportional action with a 20-min time delay (Cp/Cd/τ= 0.2/0/20), the insulin-induced hypoglycemia in depancreatized dogs could be restored to normoglycemia in the same manner as is seen in normal dogs.
3) Since the amount of glucagon infused intraportally and the amount of glucose infused for 2 hours to obtain identical blood glucose response curves was 343ng/kg and 237mg/kg respectively, it was revealed that 1ng·kg^-1·min^-1 of intraportal infusion of glucagon might evoke 0.7mg·kg^-1·min^-1 of hepatic glucose production.
The results of these present experiments indicate that the dynamic property of glucagon secretion is a proportional and derivative mode of glucose concentration, and the mode of action of glucagon on hepatic glucose production is the proportional action with firstorder delay.

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Interactions between antiserum (rabbit anti-human normal thyroglobulin-serum) and human thyroglobulin preparations (obtained from the tissues of the normal thyroid gland, thyroid adenoma, and carcinoma) were compared by inhibition effect with the binding between ¹³¹I-labeled standard thyroglobulin and antiserum, set up by a double antibody RIA.
Thyroglobulins isolated from normal glands (designated as Nor-Tg) have a high affinity to the antiserum. In contrast, thyroglobulins in follicular adenoma or adenomatous goiter (designated as Ad-Tg) decrease the potency of the affinity to the antiserum. Furthermore, thyroglobulins in papillary or follicular carcinoma (designated as Ca-Tg) markedly decrease such a potency. With the t-test, the inhibition curves of Nor-Tgs are almost parallel to each other. Most of the inhibition curves of Ad-Tgs and Ca-Tgs are not parallel to the curve of Nor-Tg (1) (P-value for non-parallelism?0.05).
Therefore, it seems that Tg preparations obtained from tumor tissue are heterogeneous in terms of specificity and/or affinity to antiserum, judging from the results of the nonparallel inhibition curves. The present results also show that the contribution of iodine content in Tg has little or no effect on the nature of Tg-immunogenecity.

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Keroconazole (Nizoral), an orally active antimycotic agent with a broad spectrum, has been reported to interfere with steroidogenesis both in patient and in vivo rat studies. It has also been shown that the same drug inhibits some P-450-catalyzed reactions in adrenal cortex mitochondria.
In the present work, we studied the inhibitory effect of Ketoconazole, along with some other known inhibitors of steroidogenesis, on the reconstituted steroid monooxygenase system, which consists of adrenodoxin, its reductase and P-450_11β as the protein components being purified from bovine adrenal cortex mitochondria.
The results indicated that; 1) Ketoconazole completely inhibited hyroxylation of deoxycorticosterone at the _11β position to form corticosterone and at the 18-position to form 18-hydroxydeoxycorticosterone. The Ki value for Ketoconazole, calculated either from the 11β-hydroxylase reaction or the 18-hydroxylase reaction, was 0.56 μM, which was comparable to the value obtained for metyrapone in the same system. 2) Ketoconazole also inhibited 18-hydroxylation of corticosterone to form 18-hydroxycorticosterone, with 50% inhibitory concentration of less than 0.03 μg/ml. The corresponding value for this inhibitor in the deoxycorticosterone 18-hydroxylase reaction was found to be 0.3 μg/ml. The contrast between these values for the two substrates is striking. Thus, in a series of reaction steps, the inhibitory effect of corticosterone to 18-hydroxycorticosterone was more potent than deoxycorticosterone to 18-hydroxycorticosterone reaction. 3) Both trilostane and o, p ' -DDD over the wide concentration range failed to inhibit any of the reconstituted P-450_11β system similar to those applied to the Ketoconazole study. NADPH-adrenodoxin reductase activity was not inhibited by either of these drugs, indicating both Trilostane and o, p'-DDD had no significant effect on the purified-reconstituted P-450_11β system.

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The shape and size of the adrenals in control subjects without adrenal disorders were studied by computed tomography (CT), and a comparative assessment of diagnostic values of ultrasonography (US) by electronic linear scanner, CT, and adrenal scintigraphy was made on 9 patients with primary aldosteronism. Adrenal imaging by scintigraphy was performed on the 5th and 6th day, or further on the 7th day after the injection of 1 mCi of Adosterol^®.
1) CT findings of the adrenals in control subjects :
Eighty-two % of 100 control right adrenals, and 89% of 100 control left adrenals were detected by CT. Seventy-seven % of the right adrenals were in linear-shape, and the others were in V-shape. The shape of the left adrenals could be classified into triangular-shape (54%), Y-shape (28%) and V-shape (18%). The mean width and thickness of the right adrenals were 28.6 ± 7.5 mm (M ± SD) and 3.8 ± 1.4 mm, respectively. Those of the left ones were 19.4 ± 5.5 mm and 5.3 ± 1.8 mm.
2) Image diagnosis of primary aldosteronism :
In 2 out of 3 patients examined by US, aldosteronomas were detected. In these 2 patients, one had 2 adenomas 2.8 × 1.7 × 1.2 cm and 1.0 × 1.0 × 2.0 cm in size, and the other had one adenoma 0.8 × 1.0 × 2.0 cm in size. On adrenal scintiscanning under dexamethasone pretreatment (DP), the isotope uptake of aldosteronoma was still seen with the disappearance of the contralateral adrenal in 7 out of 9 cases. In these 7 cases, the laterality of the tumor was confirmed. In one of the remaining 2 cases, the bilateral adrenal images were obtained regardless of DP. In the other case, of which aldosteronoma was the smallest (0.6 × 0.6 × 0.8 cm), the image of the affected adrenal with adenoma as well as the contralateral adrenal disappeared under DP. CT delineated all aldosteronomas in 8 cases examined including 2 cases in which adrenal scintiscanning failed to elucidate the localization of aldosteronoma.
These results indicated that the combination of these 3 new image diagnostic methods was available for the detection of aldosteronomas of various sizes.

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Comparative study of image diagnosis of ultrasonography (US) by linear electronic scanner, computed tomography (CT), and adrenal scintigraphy was performed in 14 patients with Cushing's syndrome. Adrenal imaging by scintigraphy was performed at the 5th and 6th day or further 7th day following the injection of 1 mCi of Adosterol^®.
1) Cushing's disease (11 cases)
US failed to detect the adrenals in 4 cases examined. Measurement of the adrenals on CT film demonstrated the enlargement of adrenals (>mean + 2SD) in 6 of 7 cases (85.7%). Scintiscanning showed the increased uptake of bilateral adrenals in 4 of 10 cases (40%). Adrenal scintigraphy with dexamethasone pretreatment (DP) still demonstrated the isotope uptake of bilateral adrenals in all of those 4 cases tested, although the other 6 cases were not studied with DP. From these findings, it was suggested that the measurement of adrenal size by CT was useful for the additional image diagnosis of Cushing's disease, and the adrenal scintigraphy with DP was also available for complementary study of Cushing's disease.
2) Cushing's syndrome due to adrenocortical adenoma (3 cases)
In one case examined by US, which had the smallest adenoma (0.6 × 1.0 × 2.0 cm) in this syndrome, the adenoma was not detected. All of 3 adrenal adenomas (2.6 × 2.6 × 2.2 cm to 0.6 × 1.0 × 2.0 cm) were detected by CT. Adrenal scintigraphy demonstrated good uptake by adrenal adenoma but no visualization of the contralateral adrenal in every case.

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The R5020 specific binding protein in the human prostate was studied to elucidate the cause for the poorer reproducibility of 4S high affinity complex sediment than that of 7-8S high affinity complex sediment. The sucrose density gradient, with a low ionic strength buffer including sodium molybdate, was used.
Charcoal assay is one of the most common methods used in steroid receptor studies. However, there is a possibility that the high amount of non-specific binding protein common in the human prostate disturbs the charcoal function which removes the free and also the loosely bound steroids from low affinity protein. In the sucrose density gradient process, charcoal treatment is necessary to obtain the apparent 7-8S peak from the 4S one because 7-8S is covered with huge 4S when the charcoal treatment is not performed. 4S complex is proved to be more sensitive than 7-8S to this form of treatment in this study. In addition, the R5020 specific binding protein is found in not only 7-8S complex but also 4S. The dissociation constant of 4S protein is identified with that in 7-8S in the low range of [3H] -R5020 (0.4-5.2 nM) using Scatchard plots, but not in the high range (1.3-10.4 nM). Thus, it seems possible that the high amount of non-specific binding protein disturbs the accurate quatification of specific binding protein in 4S.
In conclusion, the poor reproducibility of 4S complex through charcoal treatment is caused by the presence of the high amount of non-specific binding protein in the human prostate.

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Serum insulin-like growth factor I (IGF-I) (26-46) levels were determined in normal children aged 0-16y (n=111), adults (n=11), and various diseased conditions. In order to elucidate a mutual relationship between IGF-I (26-46) and growth hormone (GH) secretion, the following correlations were evaluated : 1) a correlation between IGF-I (26-46) and basal GH level (n=57), 2) a correlation between IGF-I (26-46) and GH level responding to the insulin tolerance test (ITT) (n=30), 3) a correlation between IGF-I (26-46) and an integrated concentration of GH (ICGH) in the early sleep stage (n=24). In addition, the following correlations between GH level with ITT and ICGH in the early sleep stage (n=20) and between IGF-I (26-46) and an integrated concentration of prolactin (ICPRL) in the early sleep (n=20) and overnight sleep (n=7) stages were also examined.
IGF-I (26-46) was measured according to the method of Yanaihara with minor modifications. Samples for ICGH were collected every 30 min until 4 hours after sleep by a portable continuous flow blood withdrawal pump (CORMED, MODEL ML6) at a rate of 6 ml/h. Samples for ICPRL from 13 subjects were collected by the same procedure and period as ICGH. On the other hand, samples for ICPRL from 7 subjects were collected during an overnight period. Sleep and wake cycles were almost identical in the subjects tested. Among the subjects tested with ITT and continuous blood sampling for ICGH and ICPRL, patients with pituitary dwarfism were excluded.
Serum IGF-I (26-46) levels appeared to be age-dependent, and the highest value was demonstrated in puberty. Some children under 8 years of age showed serum IGF-I (26-46) levels as low as that of pituitary dwarfism. No sexual difference was noticed in IGF-I (26-46) levels. Serum IGF-I (26-46) levels in pituitary dwarfism were apparently low and significantly increased after hGH injection. Serum IGF-I (26-46) levels in patients under 11 years of age with constitutional dwarfism and Turner's syndrome revealed an almost normal result. However, many patients over 11 years of age showed lower levels of serum IGF-I (26-46) than normal subjects, and some cases showed remarkably low levels of serum IGF-I (26-46). Serum IGF-I (26-46) levels in precocious puberty without treatment were slightly high in comparison with age-matched controls.
Correlation was observed between neither IGF-I (26-46) and basal GH nor between IGF-I (26-46) and GH response (both maximum GH level and maximum GH increase from basal level) in ITT. Additionally, no correlation was observed between GH response in ITT and ICGH in the early sleep stage. However, a statistically significant positive correlation was observed between IGF-I (26-46) and ICGH (both maximum and mean ICGH) in the early sleep stage. No correlation was noticed between IGF-I (26-46) and ICPRL (both maximum and mean ICPRL) in either the early or overnight sleep stages.
These results suggest the following :
1) When interpreting the absolute value of IGF-I (26-46), subject age should be considered because IGF-I (26-46) value changes with age. 2) Some etiological factors such as short stature seen in Turner's syndrome or constitutional dwarfism may be due to defective IGF-I. Overgrowth in precocious puberty may be due to increased IGF-I in addition to increased sex hormones. 3) Continuous stimulation of GH is important to generate IGF-I. Hence basal GH level and GH response in the provocative test do not always reflect the physiological GH action of generating IGF-I. 4) Prolactin does not play an important role generating IGF-I in the status of normal GH secretion. 5) IGF-I (26-46) is thought to be a good indicator for IGF-I.

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